Bruton's tyrosine kinase (abbreviated as Btk hereinafter) belongs to the Tee family of non-receptor tyrosine kinases that is expressed in B cells and other hematopoietic cell types (such as monocyte, mast cell). Btk plays an essential and important role in the B-cell signaling pathways and is an essential factor of B-cell survival, differentiation, proliferation and activation. B-cell signaling through the B-cell antigen receptor (BCR) leads to a wide range of biological outputs. If BCR-mediated signaling is aberrant, it causes deregulated B-cell activation and/or the formation of pathogenic auto-antibodies. Mutations in the gene encoding human Btk results in X-linked agammaglobulinemia (XLA). It is known that this disease is caused by abnormal production of immunoglobulin based on the impaired maturation of B-cells (see Nature 361, 226-233, (1993)). The clinical signs of this disease exemplify the marked decrease of B-cells in peripheral blood and the increased susceptibility to bacterial infection or the like. In addition, Btk is also known to be involved in mast cell activation or platelet physiology.
Therefore, inhibitors of Btk could be useful for treatment of an allergic disease, an autoimmune disease, an inflammatory disease, a thromboembolic disease, cancer or the like.
It has been disclosed that a pyrrolotriazine compound represented by formula (A)
wherein ring AA is aromatic; R1-A represents H or halogen; R2-A represents H or halogen; R4-A represents —OR10-A wherein R10-A represents H, (C1-C3)alkyl, optionally substituted phenyl, or optionally substituted benzyl; LA represents a bond, a divalent phenyl; R5-A represents NR18-AR19-A wherein R18-A represents H or (C1-C3)alkyl, R19-A represents H, (C1-C3)alkyl, SO2R25-A wherein R25-A represents (C1-C3)alkyl; R6-A represents H or (C1-C3)alkyl; and R7-A represents H, CN, or (C1-C3)alkyl (the definition of each group in the above described formula is excerpted), is useful for IGF-1R kinase inhibitor (From WO 2007/056170).
Furthermore, it has been described that a pyrrolotriazine compound represented by formula (B)
wherein XB and YB independently selected from O, OCO, S, SO2, CO, CO2, halogen, nitro, cyano, or XB or YB are absent; ZB is selected from O, S or N; R1-B is hydrogen, CH3, OH, OCH3, SH, SCH3, halogen, nitro, or cyano; R2-B and R3-B are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo; R4-B and R5-B are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, except that when ZB is O or S, R5-B is absent, or when ZB is nitrogen, R4-B and R5-B are not both hydrogen; R6-B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo or halogen (the definition of each group in the above described formula is excerpted), is useful for VEGF kinase inhibitor (From WO 2000/71129).
In addition, it has been disclosed that a imidazopyrimidine compound represented by formula (C)
wherein LaC is CH2, O, NH or S; ArC is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; YC is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; ZC is CO, OCO, NHCO, CS; R7-C and R8-C are independently selected from among H, unsubstituted C1-C4alkyl, substituted C1-C4alkyl, unsubstituted C1-C4heteroalkyl, substituted C1-C4heteroalkyl, unsubstituted C3-C6cycloalkyl, substituted C3-C6cycloalkyl, unsubstituted C2-C6heterocycloalkyl, and substituted C2-C6heterocycloalkyl; or R7-C and R8-C taken together from a bond; R6-C is H, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4heteroalkyl, C1-C6alkoxyalkyl, C1-C8alkylaminoalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted aryl (with the proviso that the definition of each group in the above described formula is excerpted), is useful for inhibitor of Btk (From WO2008/039218, WO 2008/121742 and WO 2010/009342).
Meanwhile, there are some protein kinases, such as Lck, Lyn, Fyn that are closely related to Btk. In particular, it is known that retinal abnormalities are observed in Lck (the Src family of non receptor-type kinases) deficient mice (See oncogene, 16, 2351-2356, (1998)).